The present invention relates generally to the field of compositions, kits, and methods for activating, expanding, or stimulating T cells. In particular, the present invention relates to pharmaceutical compositions that may be useful as vaccines or immunogenic compositions for activating, expanding, or stimulating γδ T cells.
Human γδ T cells, such as Vγ2Vδ2 T cells, are stimulated by prenyl pyrophosphates, such as isopentenyl pyrophosphate (IPP), and play important roles in mediating immunity against microbial pathogens and have potent anti-tumor activity. (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) has been identified as a metabolite in the 2-C-methyl-D-erythritol-4 phosphate (MEP) pathway for isoprenoid biosynthesis that is used by many bacteria and protozoan parasites. Here, it is found that HMBPP is the major Vγ2Vδ2 T cell antigen for many bacteria, including Mycobacterium tuberculosis, Yersinia enterocolitica, and Escherichia coli. HMBPP was a 30,000-fold more potent antigen than IPP. Using mutant bacteria, it is shown that bacterial antigen levels for Vγ2Vδ2 T cells are controlled by MEP pathway enzymes and no evidence for the production of 3-formyl-1-butyl pyrophosphate was found. Moreover, HMBPP-reactivity required only germ-line encoded Vγ2Vδ2 TCR elements and is present at birth. Bacterial HMBPP levels were shown to correlate with an ability to expand Vγ2Vδ2 T cells in vivo upon engraftment into severe combined immunodeficiency-beige (SCID-beige) mice. Thus, the production of HMBPP by a microbial-specific isoprenoid pathway plays a major role in determining whether bacteria will stimulate Vγ2Vδ2 T cells in vivo. This preferential stimulation by a common microbial isoprenoid metabolite may allow Vγ2Vδ2 T cells to respond to a broad array of pathogens using this pathway.
Another synthetic phosphoantigen, bromohydrin pyrophosphate (BrHPP)/Phosphostim, was found to transiently expand Vγ9/Vδ2 in cynomolgus monkeys, which were used as a non-human primate model. (See Sicard et al. In Vivo Immonmanipulation of Vγ9Vδ2 T cells with a Synthetic Phosphoantigen in a Preclincal Nonhuman Primate Model. J. Immunol. 2005, 175: 5471-5480). However, this transient expansion was found to return to baseline within 10-15 days. Furthermore, succession infusions of BrHPP induced less vigorous expansions, suggesting that progressive exhaustion of the response was occurring. Therefore, vaccines and immunogenic compositions that induce more long-lasting expansions of γδ T cells and that do not result in exhaustion are desirable.